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Congenital heart disease affects approximately seven in 1000 live births, and remains a significant worldwide cause of morbidity and mortality. Recurrence risk studies show that there is a substantial familial predisposition to congenital heart disease.1 It is currently estimated that approximately 20% of congenital heart disease cases can be attributed to chromosomal disorders (eg, Down's syndrome), other known congenital malformation syndromes, teratogen exposure and maternal diabetes. The remaining 80% appears to behave as a ‘complex disease’, showing aggregation within families without Mendelian segregation, suggesting the importance of multiple genetic and environmental factors. Considering all congenital heart disease phenotypes together, there is approximately a threefold higher relative risk to future siblings of a case; however, this can be substantially higher in certain conditions, for example, atrioventricular septal defect and tetralogy of Fallot.2 Genetic studies have recently made significant progress in discovering some of the influences on other cardiovascular complex diseases such as hypertension and coronary artery disease3 4; and a recent study of Tetralogy of Fallot suggested that as much as 10% of disease susceptibility could be caused by variations in the gene copy number in a variety of regions of the genome.5 In this issue of Heart, Alessandro de Luca and colleagues6 (see page 673) investigate the impact of mutations in genes determining laterality on the risk of familial transposition of the great arteries (TGA).
The investigators sought to maximise the likelihood of detecting genetic factors by studying families in which there was a proband with TGA and at least one other …